Morphine and other opiate drugs are widely used to treat severe pain but the addiction and side effects they produce often limit their use. The goal of this research is to develop a novel treatment for morphine addiction and toxicity based on an endogenous peptide, glycyl-glutamine (Gly-GIn). Gly-GIn is synthesized in brain from the opioid peptide, beta-endorphin. In preclinical studies, Gly-GIn administration to laboratory animals prevented the respiratory depression and hypotension caused by morphine without compromising morphine's ability to relieve acute pain. The proposed research will test the hypothesis that Gly-GIn inhibits morphine addiction, tolerance and dependence and determine if Gly-GIn influences morphine analgesia in experimental models of chronic pain. Aim 1 will extend preliminary evidence that Gly-GIn pretreatment prevents the acquisition of a conditioned place preference to morphine, an animal model of drug addiction that measures the rewarding or incentive effect of addictive drugs, and determine if Gly-GIn also inhibits the rewarding effects of nicotine. Aim 2 will continue preliminary studies showing that Gly-GIn pretreatment inhibits development of tolerance to morphine analgesia and reduces the severity of physical dependence. Aim 3 will test whether Gly-GIn influences morphine analgesia in experimental models of chronic neuropathic and inflammatory pain. We expect to find that Gly-GIn does not interfere with morphine therapy for these chronic pain conditions and further hypothesize that it may produce beneficial effects, that it may potentiate morphine analgesia and reduce pain hypersensitivity. PROPOSED COMMERCIAL APPLICATION: At present, there are no effective treatments for morphine addiction and toxicity that do not interfere with morphine's ability to relieve pain. The development of a compound that nullifies the rewarding effects of opiates may provide a pragmatic approach for reducing morphine's abuse potential and the ability to selectively prevent morphine's adverse effects would be of significant benefit to patients suffering severe pain.